Altered ion channels in an animal model of CMT IA

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J Neurosci. 2005 Feb 9;25(6):1470-80.

Altered ion channels in an animal model of Charcot-Marie-Tooth disease type IA.

Devaux JJ, Scherer SS.

Department of Neurology, University of Pennsylvania Medical Center,

Philadelphia, Pennsylvania 19104-6077, USA.

How demyelination and remyelination affect the function of myelinated axons is a

fundamental aspect of demyelinating diseases. We examined this issue in

Trembler-J mice, a genetically authentic model of a dominantly inherited

demyelinating neuropathy of humans. The K+ channels Kv1.1 and Kv1.2 channels

were often improperly located in the paranodal axon membrane, typically

associated with improperly formed paranodes, and in unmyelinated segments

between internodes. As in wild-type nerves, Trembler-J nodes contained Nav1.6,

ankyrin-G, betaIV-spectrin, and KCNQ2, but, unlike wild-type nerves, they also

contained Kv3.1b and Nav1.8. In unmyelinated segments bordered by myelin

sheaths, these proteins were clustered in heminodes and did not appear to be

diffusely localized in the unmyelinated segments themselves. Nodes and heminodes

were contacted by Schwann cells processes that did not have the ultrastructural

or molecular characteristics of mature microvilli. Despite the presence of

Nav1.8, a tetrodotoxin-resistant sodium channel, sciatic nerve conduction was at

least as sensitive to tetrodotoxin in Trembler-J nerves as in wild-type nerves.

Thus, the profound reorganization of axonal ion channels and the aberrant

expression of novel ion channels likely contribute to the altered conduction in

Trembler-J nerves.

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